Cachexia is a progressive atrophy of adipose tissue and skeletal muscle that occurs in more than 85% of pancreatic ductal adenocarcinoma (PDAC) patients. It is a major contributor to the mortality of patients and an independent predictor of shorter survival. Cachexia dramatically reduces the quality of life of PDAC patients and increases the risk of treatment failure and toxicity. Treatments against cachexia are palliative in nature: there is no effective therapy for cancer-associated cachexia. Recently, increased interest has focused on tackling cachexia by attempting to revert the metabolic alterations that are associated with cachexia. A key feature in cancer cachexia is the loss of adipose tissue. Studies in humans have shown that increased adipocyte lipolysis, not reduced lipogenesis or increased fat cell death, is the primary cause of fat loss in cancer cachexia. Treating cancer patients with agents that address the adipocyte dysfunction that is the basis of the cachexia, in combination with standard antineoplastic agents, may dramatically enhance their quality of life and the chances of success of the anti-tumor treatment. All enzymes known to be involved in adipocyte lipolysis (ATGL, HSL, MGLL) are serine hydrolases. Genetic ablation of adipose triglyceride lipase (ATGL) and to a lesser extent hormone sensitive lipase (HSL) can protect from cancer-associated cachexia, demonstrating that correction of the adipocyte dysfunction is indeed a viable approach to reverse cancer-associated cachexia. However, systemic inhibition of these serine hydrolases is predicted to have deleterious effects that preclude this approach to treat cachexia. For example, ATGL null mice accumulate lipid in the heart and die prematurely. Integrating phenotypic screening with chemoproteomic methods, we recently identified another serine hydrolase, Ces3, which regulates adipocyte lipolysis. Pharmacologic inhibition of Ces3 ameliorates multiple features type 2 diabetes (another condition that involves increased rate of adipocyte lipolysis) without inducing side effects. We intend to evaluate the therapeutic potential of Ces3 inhibition in pancreatic cancer-associated cachexia, and to identify additional poorly annotated serine hydrolases that may serve as targets in cancer-associated cachexia.